Antifibrotic Drugs against Idiopathic Pulmonary Fibrosis and Pulmonary Fibrosis Induced by COVID-19: Therapeutic Approaches and Potential Diagnostic Biomarkers.

The COVID-19 pandemic has had a significant impact on the health and economy of the global population. Even after recovery from the disease, post-COVID-19 symptoms, such as pulmonary fibrosis, continue to be a concern. This narrative review aims to address pulmonary fibrosis (PF) from various perspectives, including the fibrotic mechanisms involved in idiopathic and COVID-19-induced pulmonary fibrosis. On the other hand, we also discuss the current therapeutic drugs in use, as well as those undergoing clinical or preclinical evaluation. Additionally, this article will address various biomarkers with usefulness for PF prediction, diagnosis, treatment, prognosis, and severity assessment in order to provide better treatment strategies for patients with this disease.

Epidemiology of Tracheostomized Adult Patients Admitted to Specialized Weaning Centers After Acute COVID-19.

BACKGROUND: Epidemiological data on patients with COVID-19 referred to specialized weaning centers (SWCs) are sparse, particularly in low- and middle-income countries. Our aim was to describe clinical features, epidemiology, and outcomes of subjects admitted to SWCs in Argentina. METHODS: We conducted a prospective, multi-center, observational study between July 2020-December 2021 in 12 SWCs. We collected demographic characteristics, laboratory results, pulmonary function, and dependence on mechanical ventilation at admission, decannulation, weaning from mechanical ventilation, and status at discharge. A multiple logistic model was built to predict home discharge. RESULTS: We enrolled 568 tracheostomized adult subjects after the acute COVID-19 phase who were transferred to SWCs. Age was 62 [52-71], males 70%, Charlson comorbidity index was 2 [0-3], and length of stay in ICU was 42 [32-56] d. Of the 315 ventilator-dependent subjects, 72.4% were weaned, 427 (75.2%) were decannulated, and 366 subjects (64.5%) were discharged home. The mortality rate was 6.0%. In multivariate analysis, age (odds ratio 0.30 [95% CI 0.16-0.56], P < .001), Charlson comorbidity index (odds ratio 0.43 [95% CI 0.22-0.84], P < .01), mechanical ventilation duration in ICU (odds ratio 0.80 [95% CI 0.72-0.89], P < .001), renal failure (odds ratio 0.40 [95% CI 0.22-0.73], P = .003), and expiratory muscle weakness (odds ratio 0.35 [95% CI 0.19-0.62], P < .001) were independently associated with home discharge. CONCLUSIONS: Most subjects with COVID-19 transferred to SWCs were weaned, achieved decannulation, and were discharged to home. Age, high-comorbidity burden, prolonged mechanical ventilation in ICU, renal failure at admission, and expiratory muscle weakness were inversely associated with home discharge.

Evaluation of dapsone and its synthetic derivative DDS­13 in cancer in vitro.

The present study highlighted the repositioning of the drug dapsone (DDS) for cancer therapy. Due to its mechanism of action, DDS has a dual effect as an antibiotic and as an anti-inflammatory/immunomodulator; however, at high doses, it has important adverse effects. The derivative DDS-13 [N,N'-(sulfonyl bis (4,1-phenylene)) dioctanamide] was synthesized through an N-acylation reaction to compare it with DDS. Its cytotoxic effects in cancer cells (DU145 and HeLa) and non-cancer cells (HDFa) were observed at concentrations ranging 0.01-100 µM and its physicochemical/pharmacokinetic properties were analyzed using the SwissADME tool. The objectives of the present study were to evaluate the anticancer activity of both DDS and DDS-13 and to identify the physicochemical and pharmacokinetic properties of DDS-13. The results showed that DDS-13 presented a cytotoxic effect in the DU145 cell line (IC50=19.06 µM), while DDS showed a cytotoxic effect on both the DU145 (IC50=11.11 µM) and HeLa (IC50=13.07 µM) cell lines. DDS-13 appears to be a good cytotoxic candidate for the treatment of prostate cancer, while DDS appears to be a good candidate for both cervical and prostate cancer. Neither candidate showed a cytotoxic effect in non-cancerous cells. The different pharmacokinetic properties of DDS-13 make it a new candidate for evaluation in preclinical models for the treatment of cancer.

Triterpene Derivatives as Potential Inhibitors of the RBD Spike Protein from SARS-CoV-2: An In Silico Approach.

The appearance of a new coronavirus, SARS-CoV-2, in 2019 kicked off an international public health emergency. Although rapid progress in vaccination has reduced the number of deaths, the development of alternative treatments to overcome the disease is still necessary. It is known that the infection begins with the interaction of the spike glycoprotein (at the virus surface) and the angiotensin-converting enzyme 2 cell receptor (ACE2). Therefore, a straightforward solution for promoting virus inhibition seems to be the search for molecules capable of abolishing such attachment. In this work, we tested 18 triterpene derivatives as potential inhibitors of SARS-CoV-2 against the receptor-binding domain (RBD) of the spike protein by means of molecular docking and molecular dynamics simulations, modeling the RBD S1 subunit from the X-ray structure of the RBD-ACE2 complex (PDB ID: 6M0J). Molecular docking revealed that at least three triterpene derivatives of each type (i.e., oleanolic, moronic and ursolic) present similar interaction energies as the reference molecule, i.e., glycyrrhizic acid. Molecular dynamics suggest that two compounds from oleanolic and ursolic acid, OA5 and UA2, can induce conformational changes capable of disrupting the RBD-ACE2 interaction. Finally, physicochemical and pharmacokinetic properties simulations revealed favorable biological activity as antivirals.

Therapeutic Effects of Coumarins with Different Substitution Patterns.

The use of derivatives of natural and synthetic origin has gained attention because of their therapeutic effects against human diseases. Coumarins are one of the most common organic molecules and are used in medicine for their pharmacological and biological effects, such as anti-inflammatory, anticoagulant, antihypertensive, anticonvulsant, antioxidant, antimicrobial, and neuroprotective, among others. In addition, coumarin derivates can modulate signaling pathways that impact several cell processes. The objective of this review is to provide a narrative overview of the use of coumarin-derived compounds as potential therapeutic agents, as it has been shown that substituents on the basic core of coumarin have therapeutic effects against several human diseases and types of cancer, including breast, lung, colorectal, liver, and kidney cancer. In published studies, molecular docking has represented a powerful tool to evaluate and explain how these compounds selectively bind to proteins involved in various cellular processes, leading to specific interactions with a beneficial impact on human health. We also included studies that evaluated molecular interactions to identify potential biological targets with beneficial effects against human diseases.

Influence of Galactooligosaccharides on the Positive Effect of Plant Sterol-Enriched Beverages on Cardiovascular Risk and Sterol Colon Metabolism.

In the present study, the impact of galactooligosaccharide (GOS) addition to a plant sterol (PS)-enriched beverage on the hypocholesterolemic effect and on the bioavailability and colonic metabolization of sterols was evaluated. A crossover trial was undertaken in postmenopausal women who intook a PS-enriched (2 g PS/day) or PS-GOS-enriched beverage (2 g PS/day and 4.3 g GOS/day) for 6 weeks. The presence of GOS did not modify the hypocholesterolemic effect of the PS-enriched beverage (total- and low-density lipoprotein-cholesterol reductions) or sterol bioavailability (increments of serum markers of dietary PS intake and of cholesterol synthesis). The consumption of both beverages led to an increase of sterol and metabolite excretion (with the exception of coprostanol, which decreased) and to slight changes in women's capacities for sterol conversion, regardless of the GOS presence. This study demonstrates the suitability of simultaneous enrichment with PS and GOS in milk-based fruit beverages, considering their hypocholesterolemic effect.

Synthesis, In Vitro, and In Silico Analysis of the Antioxidative Activity of Dapsone Imine Derivatives.

Dapsone (DDS) is an antibacterial drug with well-known antioxidant properties. However, the antioxidant behavior of its derivatives has not been well explored. In the present work, the antioxidant activity of 10 dapsone derivatives 4-substituted was determined by an evaluation in two in vitro models (DPPH radical scavenging assay and ferric reducing antioxidant power). These imine derivatives 1-10 were obtained through condensation between DDS and the corresponding aromatic aldehydes 4-substuited. Three derivatives presented better results than DDS in the determination of DPPH (2, 9, and 10). Likewise, we have three compounds with better reducing activity than dapsone (4, 9, and 10). In order to be more insight, the redox process, a conceptual DFT analysis was carried out. Molecular descriptors such as electronic distribution, the total charge accepting/donating capacity (I/A), and the partial charge accepting/donating capacity (ω+/ω-) were calculated to analyze the relative donor-acceptor capacity through employing a donor acceptor map (DAM). The DFT calculation allowed us to establish a relationship between GAPHOMO-LUMO and DAM with the observed antioxidant effects. According to the results, we concluded that compounds 2 and 3 have the lowest Ra values, representing a good antioxidant behavior observed experimentally in DPPH radical capturing. On the other hand, derivatives 4, 9, and 10 display the best reducing capacity activity with the highest ω- and Rd values. Consequently, we propose these compounds as the best antireductants in our DDS imine derivative series.

Hyperglycemia and Angiotensin-Converting Enzyme 2 in Pulmonary Function in the Context of SARS-CoV-2 Infection.

Since the appearance of the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 in China, diabetes mellitus (DM) and hyperglycemia in patients infected with SARS-CoV, represent independent predictors of mortality. Therefore, metabolic control has played a major role in the prognosis of these patients. In the current pandemic of coronavirus disease 19 (COVID-19), multiple studies have shown that DM is one of the main comorbidities associated with COVID-19 and higher risk of complications and death. The incidence and prevalence of COVID-19 complications and death related with hyperglycemia in patients with or without DM are high. There are many hypotheses related with worse prognosis and death related to COVID-19 and/or hyperglycemia. However, the information about the interplay between hyperglycemia and angiotensin-converting enzyme 2 (ACE2), the critical receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the context of SARS-CoV-2 infection, is almost null, but there is enough information to consider the possible participation of hyperglycemia in the glycation of this protein, unleashing a pool of reactions leading to acute respiratory distress syndrome and death in patients with COVID-19. In this document we investigated the current evidence related with ACE2 as a key element within the pathophysiological mechanism related with hyperglycemia extrapolating it to context of SARS-CoV-2 infection and its relationship with worse prognosis and death for COVID-19.

Security and Violence Perception of Medical Interns during Social Service Practice in Mexico.

The increase of insecurity levels in Mexico, as well as the fact that violence is a frequent experience among health personnel, motivated this study whose purpose was to evaluate the perception of security and violence that social service medical interns (SSMI) had on the institutions and localities where they carried out their social work and make visible the main types of violence to which they were exposed. This was a cross-sectional study, based on a perception survey self-administered to 157 SSMI from Zacatecas, in Mexico. A high proportion of the participants (75.8%) stated that they were victims of violence, describing 134 incidents; however, only 33.6% of SSMI made an official report. The reported incidents were related to organized crime (31.9%), verbal violence (20.6%), violence by the authorities (14.7%) and sexual harassment (11.8%). One hundred percent of the victims of sexual harassment were women (p = 0.039). According to the above, it is a priority to generate strategies to prevent and reduce the risk of exposure to the violence generated in the medical units and communities where SSMI carry out their activities as medical graduates, as well as, to efficiently process formal violence reports to promote a safe environment that favors the fulfillment of the practice of SSMIs in Mexico.

Expression Levels of Inflammatory and Oxidative Stress-Related Genes in Skin Biopsies and Their Association with Pityriasis Alba.

Background and objectives: Pytiriasis alba (PA) is a common skin disorder which affects 80% of children between six and 16 years. The etiology of PA is unclear, but hypo-pigmented patches in photo-exposed zones characterize the disease. Because the high ultraviolet exposition of the skin promotes an acute inflammatory response and an increase of oxidative stress (OS), this study aimed to evaluate the expression levels of inflammatory and OS-related genes in skin biopsies, and their association with PA. Materials and Methods: A cross-sectional study was carried out. Skin biopsies of the lesion sites and healthy skin (controls) from 16 children with PA were evaluated. The tissue expression of IL-4, IL-6, IL-17A, TNFα, INFγ, IL-1ß, SOD1, and HMOX1 was analyzed by qRT-PCR, using SYBR Green and glyceraldehyde-3-phosphate dehydrogenase gene as the endogenous control. Results: There were differences in the ΔCq values of HMOX1, SOD1, IL-6, and IFNγ between tissue with lesions and healthy skin (p < 0.05). Compared with healthy skin, IL-6, IFNγ, HMOX1, and SOD1 were predominantly under-expressed in the lesion sites. However, 25% of skin biopsies with lesions showed over-expression of these four genes. Positive correlations between the expression of IL-6 and HMOX1, SOD1, and IFNγ (p < 0.05) were also observed. Conclusions: Our results suggest the presence of molecular stages of PA, defined according to the over-expression (first stage) or under-expression (second stage) of the HMOX1, SOD1, IL-6, and IFNγ genes in abnormal skin tissue. These findings may have implications for the selection of treatment for PA-related lesions.

Impact of a Plant Sterol- and Galactooligosaccharide-Enriched Beverage on Colonic Metabolism and Gut Microbiota Composition Using an In Vitro Dynamic Model.

A beverage enriched with plant sterols (1 g/100 mL) and galactooligosaccharides (1.8 g/100 mL) was subjected to a dynamic gastrointestinal and colonic fermentation process to evaluate the effect on sterol metabolism, organic acid production, and microbiota composition. Production of sterol metabolites (coprostanol, methylcoprostanol, ethylcoprostenol, ethylcoprostanol, and sitostenone) was observed in the transverse colon (TC) and descending colon (DC) vessels in general, from 24 and 48 h, respectively. Microbial activity was assessed through the production of organic acids, mainly acetate in all colon vessels, lactate in the AC, and butyrate and propionate in the TC and DC. A higher diversity in the microbial community was found in the TC and DC, in accordance with a higher sterol metabolism and organic acid production. Although the prebiotic effect of galactooligosaccharides was not detected, changes in microbiota composition (an increase in the Parabacteroides genus and the Synergistaceae and Lachnospiraceae families) indicated an enhancement of sterol metabolism.

Modeling the Antileukemia Activity of Ellipticine-Related Compounds: QSAR and Molecular Docking Study.

The antileukemia cancer activity of organic compounds analogous to ellipticine representes a critical endpoint in the understanding of this dramatic disease. A molecular modeling simulation on a dataset of 23 compounds, all of which comply with Lipinski's rules and have a structure analogous to ellipticine, was performed using the quantitative structure activity relationship (QSAR) technique, followed by a detailed docking study on three different proteins significantly involved in this disease (PDB IDs: SYK, PI3K and BTK). As a result, a model with only four descriptors (HOMO, softness, AC1RABAMBID, and TS1KFABMID) was found to be robust enough for prediction of the antileukemia activity of the compounds studied in this work, with an R2 of 0.899 and Q2 of 0.730. A favorable interaction between the compounds and their target proteins was found in all cases; in particular, compounds 9 and 22 showed high activity and binding free energy values of around -10 kcal/mol. Theses compounds were evaluated in detail based on their molecular structure, and some modifications are suggested herein to enhance their biological activity. In particular, compounds 22_1, 22_2, 9_1, and 9_2 are indicated as possible new, potent ellipticine derivatives to be synthesized and biologically tested.

Diabetic Foot Ulcers: Current Advances in Antimicrobial Therapies and Emerging Treatments.

Diabetic foot ulcers (DFUs) are very important diabetes-related lesions that can lead to serious physical consequences like amputations of limbs and equally severe social, psychological, and economic outcomes. It is reported that up to 25% of patients with diabetes develop a DFU in their lifetime, and more than half of them become infected. Therefore, it is essential to manage infection and ulcer recovery to prevent negatives outcomes. The available information plays a significant role in keeping both physicians and patients aware of the emerging therapies against DFUs. The purpose of this review is to compile the currently available approaches in the managing and treatment of DFUs, including molecular and regenerative medicine, antimicrobial and energy-based therapies, and the use of plant extracts, antimicrobial peptides, growth factors, ozone, devices, and nano-medicine, to offer an overview of the assessment of this condition.

Serum cytokine, chemokine, and growth factor profiles and their modulation in inflammatory bowel disease.

Ulcerative colitis (UC) and Crohn disease (CD) are the most common forms of inflammatory bowel disease (IBD). Because these subtypes of IBD are characterized by periods of activity and remission, an understanding of the modulation of biochemical markers with the clinical features of IBD or its treatment, may be useful for determining the correct treatment protocol.This study aimed to evaluate the serum levels of 27 protein biomarkers to determine their association with IBD, correlation with clinical findings of disease, and modulation according to the pharmacologic therapy.A case-control study was carried out in Zacatecas, Mexico. The 27 protein profiles of serum from 53 participants (23 UC, 11 CD, and 19 controls) were evaluated using the Pro Human Cytokine 27-Plex immunoassay (Bio-Rad).Considering the controls as a reference, the group with IBD endoscopic activity showed higher serum levels of granulocyte colony-stimulating factor (G-CSF), interleukin 1 receptor antagonist (IL-1Ra), and platelet-derived growth factor BB (PDGF-BB) (P < .05). Interferon-induced protein 10 (IP-10) was associated with extraintestinal symptoms of disease (P = .041). Both PDGF-BB and interleukin 6 (IL-6) showed the strongest correlations with clinical features of IBD. Levels of IL-6, IL-7, and monocyte chemoattractant protein 1 were higher with 5-aminosalicylic acid (5-ASA) + Azathioprine therapy than controls (P < .05). Combined therapy with 5-ASA + Adalimumab led to the strongest changes in marker modulation: IL-4, IL-5, IL-15, and PDGF-BB, were upregulated (P < .05).Elevated serum levels of G-CSF, IL-1Ra, and PDGF-BB were associated with IBD endoscopic activity, and of IP-10 with extraintestinal manifestations of IBD. Combined therapy of 5-ASA + Adalimumab produced significant upregulation of IL-4, IL-5, IL-15, and PDGF-BB. This information may be useful for deciding on the course of pharmacologic therapy for patients with IBD and for generating new therapy alternatives to improve the outcome of patients with IBD.

A positive impact on the serum lipid profile and cytokines after the consumption of a plant sterol-enriched beverage with a milk fat globule membrane: a clinical study.

The hypocholesterolemic effect and the modification of serum biomarkers of a dietary plant sterol (PS) intake, cholesterol precursors and cytokines after the consumption of milk-based fruit beverages with a milk fat globule membrane were evaluated by a randomized, double-blind, crossover, multiple dose bioavailability study. Postmenopausal women (n = 38) consumed daily 250 mL of a beverage with or without 2 g of PS added during 6 weeks in each of the study periods. With the intake of the PS-added beverage, significant decreases (mg dL-1) in serum total cholesterol (pre-treatment: 220.0 ± 27.8 vs. post-treatment: 212.9 ± 25.8; p < 0.05) and LDL-cholesterol (129.4 ± 28.5 vs. 121.7 ± 24.4; p < 0.05) were detected. The cholesterol precursor lathosterol (11.2%), markers of the dietary PS intake (campesterol 43.1% and ß-sitosterol 32.5%), and anti-inflammatory IL-10 cytokine (22.5%) increased significantly, with a concomitant significant reduction in pro-inflammatory IL-1ß (6.7%). No variations in HDL-cholesterol, other sterols (desmosterol and stigmasterol) or cytokines (IL-6, IL-8, IL-12p70 and TNF-α) were detected. These results indicated that this kind of PS-enriched milk-based fruit beverage is suitable during the period of clinical intervention, and its consumption may be an adequate way to improve PS functionality since a significant reduction in cholesterol levels has been observed. Therefore, the intake of this beverage could contribute to reduce the risk of cardiovascular disease also obtaining a beneficial effect on the serum inflammatory status in postmenopausal women.

The impact of galactooligosaccharides on the bioaccessibility of sterols in a plant sterol-enriched beverage: adaptation of the harmonized INFOGEST digestion method.

The effect of the addition of galactooligosaccharides (GOS) on sterol bioaccessibility in three plant sterol (PS)-enriched milk-based fruit beverages (without GOS addition (MfB) and with 2.5 g (MfB-G2) and 5.0 g (MfB-G5) GOS per 250 mL) was evaluated after micellar gastrointestinal digestion. Cholesterol bioaccessibility was very similar among beverages, though a slight significant increase (from 80% to 85%) was observed by the addition of 5.0 g GOS. The addition of GOS did not affect total PS bioaccessibility (≈37%). Based on the results obtained after micellar digestion, it has been demonstrated that these beverages could be a suitable food matrix for simultaneous enrichment with PS and GOS. The harmonized in vitro digestion model INFOGEST was applied to the MfB beverage, but the cholesterol content could not be quantified due to its contribution of bile salts. Hence, it was proposed: (i) a change in porcine bile salt concentration from 10 mM to 1.4 mM (in order to compare with micellar digestion); or (ii) a change of bile salt origin (bovine instead of porcine), maintaining physiological concentration (10 mM, INFOGEST condition). Both options allowed cholesterol quantification, with bioaccessibilities of 62% (reduction of bile salts) and 38% (replacement of the bile salt source), whereas plant sterol bioaccessibilities were 22% and 14%, respectively. Therefore, the change of bile salt origin maintaining INFOGEST concentration is proposed as a method to evaluate sterol (cholesterol and PS) bioaccessibility in these beverages, demonstrating the need for the selection of appropriate conditions of the INFOGEST harmonized method according to the food matrix and compounds to be determined.

Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo, and in silico studies.

Hit, Lead & Candidate Discovery Protein tyrosine phosphatase 1B (PTP-1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin-signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP-1B inhibition as main mechanism of action. Furthermore, derivatives 1-7 were submitted in vitro to enzymatic PTP-1B inhibition being 3, 5, and 7 the most active compounds (IC50  = 5.6, 4.7, and 4.6 µM, respectively). In addition, results were corroborated with in silico docking studies with PTP-1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of -7.48 Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of -6.43 kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50 mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin-dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p < .05).

Circulating levels of specific members of chromosome 19 microRNA cluster are associated with preeclampsia development.

PURPOSE: To perform serum microRNA expression profiling to identify members of chromosome 19 miRNA cluster involved in preeclampsia development. METHODS: Serum chromosome 19 miRNA cluster microRNA expression profiling was evaluated at 12, 16, and 20 gestational weeks and at the time of preeclampsia diagnosis, in women who developed preeclampsia (WWD-PE; n = 16) and controls (n = 18) using TaqMan low density array plates. RESULTS: A total of 51 chromosome 19 microRNA cluster members were evaluated. The circulating hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, were differentially expressed between groups (P < 0.05). Compared with controls, serum levels of hsa-miR-518f-3p at 20 GW were useful for identifying WWD-Mild-PE (P = 0.035) and WWD-Severe-PE (P = 0.007). CONCLUSIONS: Serum hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, are differentially expressed between WWD-PE and controls and their role in the development of preeclampsia should be investigated further.

Maternal distress and the development of hypertensive disorders of pregnancy.

Despite the implementation of programmes to improve maternal health, maternal and foetal mortality rates still remain high. The presence of maternal distress and its association with the development of pregnancy hypertensive disorders is not well established. The aim of this study was to evaluate the association between maternal distress and the development of hypertensive disorders in pregnancy in a prospective cohort of 321 Mexican women. Symptoms of maternal distressing were evaluated at week 20th of gestation using the General Health Questionnaire. The presence of acute somatic symptoms, social dysfunction, anxiety and insomnia increased the odds of developing a pregnancy hypertensive disorder by 5.1-26.4 times in study population (p values < .05). Our results support the participation of maternal distress in the development of hypertensive disorders of pregnancy. The implementation of effective programmes prioritising risk factors during pregnancy including the presence of maternal distressing factors is recommended. Impact statement What is already known on this subject: Changes in the nervous, endocrine, and immune systems have been observed in pregnant women with distress conditions leading to gestational disorders. What do the results of this study add: The presence of acute somatic symptoms, social dysfunction, anxiety and insomnia increased the developing of hypertensive disorders in Mexican population. What are the implications of these findings for clinical practice and/or further research: These findings may contribute to a better understanding of the role of the maternal stress in the development of hypertensive disorders of pregnancy, and in the implementation of effective programmes for clinical practice prioritising risk factors during pregnancy, including the presence of maternal distressing factors.

In vitro and in silico PTP-1B inhibition and in vivo antidiabetic activity of semisynthetic moronic acid derivatives.

Six derivatives (1-6) of moronic acid were semi-synthesized and their in vitro protein tyrosine phosphatase 1B (PTP-1B) inhibition activity assessed. Derivatives 2 (IC50=10.8 ± 0.5 µM) and 6 (IC50=7.5 ± 0.1 µM) displayed the most potent inhibitory activity. Therefore, they (50mg/Kg) were tested for their antidiabetic effect in vivo using a non-insulin dependent diabetes mellitus rat model. The results indicated that they decrease plasma glucose levels during all the experiment (p <0.05). Docking analysis of 2 and 6 with PTP-1B orthosteric site A and allosteric site B, showed that 2 had polar and Van der Waals interactions in both sites with Val49, Gln262, Met258, Phe182, Ala217, Ile219 and Gly259, displaying more affinity for site A. Compound 6 showed polar interaction with Gln262 and Van der Waals with Val49, Ile219, Gly259, Arg254, Ala27, Phe52, Met258, Asp48 and Phe182, suggesting that the potential binding site is localized in site B, close to the catalytic site A. Therefore, derivatives 2 and 6 have potential for the development of antidiabetic agents.